The loss of muscle mass and function in older adults during bed rest is facilitated by defects in the regulation of muscle protein metabolism, including an impaired ability to mount an anabolic response to a mixed nutrient meal. We propose that low-intensity exercise and supplementing daily meals with leucine will independently and synergistically reduce the deleterious effects of inactivity on skeletal muscle and facilitate recovery during rehabilitation. Metabolic measures will include: a) nutrient and exercise-specific markers of translation initiation; b) skeletal muscle protein synthesis; and c) a novel breath test of glucose tolerance. Morphologic and functional measures will include: a) muscle mass and body composition; b) muscle strength and function; and c) motor activation. We will test the following hypotheses in older men and women (65-80 years) during 7 days of bed rest followed by 7 days of inpatient rehabilitation: 1. Inactivity-induced metabolic dysregulation will blunt the anabolic response to meals, facilitating a loss of lean muscle mass, glucose tolerance and functional capacity that is partially restored during rehabilitation. 2. Supplementing daily meals with leucine will maintain nutrient-stimulated translation initiation and preserve the anabolic response to meal ingestion. This will partially preserve lean muscle mass and function during bed rest and facilitate the recovery of functional and metabolic capacity during rehabilitation. 3. Daily low-intensity exercise will preserve motor unit activation, stimulate the exercise-regulated signaling pathway and normalize the anabolic response to meal ingestion. This will partially preserve glucose tolerance, lean muscle mass and function during bed rest and facilitate rehabilitation. 4. Leucine-supplemented meals combined with low-intensity exercise will be a more effective stimulus than either intervention alone, preserving glucose tolerance, lean muscle mass and function during bed rest and facilitating a greater increase in functional and metabolic capacity during rehabilitation. This translational project will provide mechanistic and practical insight into strategies to reduce the negative consequences of physical inactivity and promote rehabilitation in aging muscle. Our novel, minimally invasive and clinically interventions have direct application for older hospitalized patients at risk of accelerated muscle loss and diminished functional capacity. PUBLIC HEALTH RELEVANCE: Older adults are at increased risk of being hospitalized or bedridden and experiencing a host of negative health outcomes including impaired insulin action, loss of lean muscle and bone mass and strength and increased morbidity and mortality. Unfortunately, current treatment options often fail when confronted with the practical realities of bed rest in aging or clinical populations. Our goal is to reduce the negative consequences of physical inactivity and promote rehabilitation in aging muscle by focusing on two novel interventions - low intensity exercise and dietary supplementation.